The compound cyclosporine (cyclosporin A) has found wide use since its introduction in the fields of organ transplantation and immunomodulation, and has brought about a significant increase in the success rate for transplantation procedures. However, unsatisfactory side-effects associated with cyclosporine, such as nephrotoxicity, have led to a continued search for immunosuppressant compounds having improved efficacy and safety.
Recently, several classes of macrocyclic compounds having potent immunomodulatory activity have been discovered. Okuhara et al., in European Patent Application No. 184162, published Jun. 11, 1986, disclose a number of macrocyclic compounds isolated from the genus Streptomyces. The immunosuppressant FK-506, isolated from a strain of S. tsukubaensis, is a 23-membered macrocyclic lactone represented by formula 1a, below. Other related natural products, such as FR-900520 (1b) and FR-900523 (1c), which differ from FK-506 in their alkyl substituent at C-21, have been isolated from S. hygroscopicus yakushimnaensis. Yet another analog, FR-900525, produced by S. tsukubaensis, differs from FK-506 in the replacement of a pipecolic acid moiety with a proline group.
FR-900520, also known as ascomycin, has been previously disclosed by Arai et al. in U.S. Pat. No. 3,244,592, issued Apr. 5, 1966, where the compound is described as an antifungal agent. Monaghan, R.L., et al., on the other hand, describe the use of ascomycin as an immunosuppressant in European Patent Application No. 323865, published Jul. 12, 1989.
Although the immunosuppressive activity of FK-506 has been clinically confirmed, toxicity in mammals has limited its utility. The activity of FK-506 has, however, prompted efforts to discover novel analogs of FK-type compounds which possess superior properties. These efforts include the chemical modification of these macrocycles, including the preparation of small synthetic fragments of FK-type derivatives; a thermal rearrangement of a variety of derivatives of FK-506 which expands the macrocyclic ring by two carbons; and modifications which include methyl ether formation at the C-32 and/or C-24 positions, oxidation of the C-32 alcohol to a ketone, and epoxide formation at the C-9 position. ##STR2## Chemical derivatization of FK-type compounds at the C-32 position has been an especially promising area of research. There is therefore an ongoing need for chemical syntheses and intennediates by means of which such derivatives may be prepared. Accordingly, an object of the present invention is to provide synthetic processes for the preparation of C-32-modified FK-type compounds from starting materials obtained, directly or indirectly, by fermentation. A further object of the invention is to provide novel chemical intermediates which are useful in such synthetic processes.